The general objective of this research project is to elucidate the molecular pathogenesis of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL), a heterogeneous group of malignancies derived from germinal center (GC) B cells and including Burkitt lymphoma (AIDS-BL), diffuse large cell lymphoma (AIDS-DLCL) and pleural effusion lymphoma (PEL). Based on new technology and recent novel findings, the research project is aimed at: 1) analyzing the phenotype of AIDS-NHL subtypes by gene expression profiling. In particular, we will use this new technology to: a) develop a molecular classification of AIDS-NHl; b) define their normal B cell counterpart; and c) identify genes specifically expressed in AIDS-NHL and pursue them as potential pathogenetic, diagnostic, and, eventually, therapeutic targets. 2) determining the pathogenetic role in AIDS- NHL of aberrant somatic hypermutation, a novel mechanism of genetic lesion identified in B cell lymphomagenesis and recently shown to be associated also with AIDS-NHL. We will search for genes targeted by aberrant somatic hypermutation in AIDS-NHL and investigate the role of specific mutations in altering the function of the cMYC and PIMl oncogenes in vitro and in vivo in transgenic animals. The results of these studies should provide novel insights into the mechanisms leading to lymphomagenesis in HIV infected individuals, and identify targets for improved diagnosis and therapy.